Ch6-Mutations and DNA Repair Mechanisms

Introduction to Genetic Analysis

  • Key Authors: Anthony J. F. Griffiths, Susan R. Wessler, Sean B. Carroll, John Doebley.
  • Focus Areas: Mutation and repair, including the molecular nature of mutations and repair mechanisms.

Types of Mutations

  • Somatic Mutations: Occur in non-germline cells; not passed to offspring; affect individual.
  • Germline Mutations: Occur in sperm or oocyte cells; passed to offspring; heritable.
    • Importance: Fuel evolution by generating phenotypic variation.

Mutation Characteristics

  • Spontaneous Mutations: Occur naturally without external influence.
  • Induced Mutations: Caused by mutagens (chemical or physical agents).
  • Mutation Rate (µ): Frequency of mutations during DNA replication; influenced by organism characteristics, gene size, etc.

Consequences of Mutations

  • Different mutations can lead to varying effects:
    • Silent Mutations: No effect on protein function; same amino acid coded.
    • Missense Mutations: Change in amino acid; can be either conservative (similar properties) or non-conservative (dissimilar properties).
    • Nonsense Mutations: Premature stop codon; truncated protein, often severe impact.
    • Frameshift Mutations: Caused by insertions/deletions that disrupt reading frame; typically severe.

Causes of Mutations

  • DNA Polymerase Slippage: Leads to insertions/deletions (indels) during replication.
  • Mispairing: Rare tautomeric forms of bases can pair incorrectly, e.g., A with C or G with T.
  • Chemical Damage: Reactive Oxygen Species (ROS) lead to DNA damage and mutations.

Types of DNA Damage

  • Abasic Sites: Loss of a base due to depurination.
  • Deamination: Loss of an amine group; alters base pairing.
  • Oxidative Damage: Caused by ROS, leading to mutations and replication issues.

DNA Repair Mechanisms

  • Base Excision Repair (BER): Removes damaged bases and repairs using the non-damaged strand as a template.
  • Nucleotide Excision Repair (NER): Repairs bulky damage; removes a larger section of DNA.
  • Mismatch Repair (MMR): Corrects replication errors, removing and resynthesizing mismatched bases.
  • Homologous Recombination (HR): Uses a homologous sequence for repair; more accurate repair method.
  • Non-Homologous End Joining (NHEJ): Joins broken DNA ends without a template; prone to errors.

The Ames Test

  • Purpose: Assesses mutagenicity of compounds using revertant bacteria (e.g., Salmonella).
  • How It Works: Mutant strains requiring histidine for growth are treated with suspected mutagens; increased revertant growth indicates mutagenic potential.

Implications of DNA Repair Deficiencies

  • Defective DNA repair mechanisms can lead to increased cancer risk.
    • Examples: Xeroderma pigmentosum (defective NER leads to UV sensitivity), HNPCC (defective MMR leads to higher cancer rates).
  • Overall Outcome: While mutations contribute to evolution, they also pose risks to organism viability.